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fantastic animation thanks for posting, i spent an hour on thier website and some how missed it or perhaps it is very new, i suspect the later

the perfection of this great man Eigen getting nobel prize in math at young age and then at 70 years old thinking of applying his math theory to biology and possibly solving the hiv treatment puzzle is a elegant thing, for his intellect,

it is kind of like putting a mistake into the pattern your grandma was knitting or crocheting in fact after watching so many dna and rna animations i was thinking recently it reminds me so so much of knitting or crocheting

if there is enough errors added to the pattern (the hiv dna) eventually the pattern is not recognizable

in latin the word for net or mesh or lace is labyrinth and the women in portugal and its colonies still weave these amazing labyrinths of white thread ...

and in the texts of greece they said these women were actually weaving the actual universe together

kind of a myth

now we have kp 1212 which weaves a different color thread into the dna of hiv and makes it unviable

i have so much hope

but then i worry that it will not succed

they are doing this at the top universities in the usa

the clinical trial

if you know anyone who is highly resistant or having alot of troubles with medsor been on meds along time

Excepting a description on how it work, can't found anything about the outcome of the phase I.I do understand that these information are confidential, and that probably the results of the Phase I were encouraging (as the Phase II has started), but short comments such as "outstanding result" will have been most appreciated.

Wow that animation is so cool it got me as excited as kid on Christmas morning. Let's hope and pray this 'present' really gets delivered. I just love it when great thinkers use their gifts creatively to solve problems in novel ways - especially when one of those problems is mine!

Ok, on the pragmatic side, I considered trying to figure out how to invest in this company, but I suspect there is no way without being an institution or very wealthy and going through their VC underwriter. If anyone has any experience or idea about this, would appreciate sharing.

Excepting a description on how it work, can't found anything about the outcome of the phase I.

Yes, Phase 1 showed the drug to be safe and quite well tolerated. However, it was only based on participants receiving the drug for 14 days (because this was all that could be supported given animal safety data). Apparently it also suggested a positive effect on viral load (although this finding obviously wasn't the subject of this phase).

Phase 2 is ongoing and is based on four months of therapy (because there now is animal safety data to warrant this length).

That interview was very instructive, thanks. Even before results of phase II are published, if a big pharma company makes a bid for, or buys Koronis, that will be a very very strong sign that this new drug will really work. From the interview, we can see that Koronis is not interested in atracting small private investors, they want a single huge investor to associate with them. The same thing happened with Tibotec, when it was acquired by J&J in 2002. Now, if no big pharma company gest interested in Koronis, that is a bad omen.

KP-1461 is a novel antiretroviral agent that works as a selective viral mutagen through a process called Viral Decay Acceleration. Unlike conventional ART, KP-1461 demonstrates irreversible viral extinction in vitro. This phase I-b study shows that treatment with KP-1461 is generally safe and well tolerated when administered over 14 days at doses of 400, 800, and 1600 mg every 12 hours to HIV-infected subjects. Whether the notable effect seen in the in vitro studies is replicated in vivo is the subject of an ongoing phase 2 study.

Background

KP-1461 is a novel, first-in-class, therapeutic agent for the treatment of human immunodeficiency virus (HIV) infection. KP-1461 is an oral prodrug of KP-1212, which in vitro irreversibly extinguishes HIV through the process of Viral Decay Acceleration (Harris).

KP-1461 is a deoxycytidine analog that acts as a selective viral mutagen. As a result of its flexible structure, KP-1461 induces base pairing errors. This accumulation of errors leads to a progressive reduction of viral fitness and eventual error catastrophe and population collapse. The naturally high error rate in the incorporation of bases during HIV transcription and the information dense genome allow the virus to escape immune system responses and to develop resistance to antiviral drugs. As a result, HIV exists as a quasispecies containing related variants with differing degrees of fitness, virulence and pathogenicity. The high inherent error rate, lack of RT proofreading capability, and no known ability to repair a DNA-RNA heteroduplex make HIV and other viruses particularly vulnerable to additional errors that could adversely affect viral population survival (Overbaugh; Eigen; Anderson).

KP-1461 contains an unmodified sugar, allowing continual chain elongation by RT, with a modified base that appears ambiguous to the complementary base. Through a tautomeric process, KP-1461 can pair with either guanosine or adenosine, thus creating G-to-A and C-to-T errors (Loeb). Base pairing errors are incorporated randomly throughout the viral genome and persist through subsequent replication cycles. Based on in vitro data where HIV was ablated, modeling suggests that at least 8 to 12 weeks of treatment may be required before a significant antiviral effect in humans is noted.

Consequent to its mechanism of action, KP-1461 does not appear to exert the same type of selective pressure on the virus as conventional antiretrovirals. This may reduce, or even preclude, the development of KP-1461-resistant variants. The ability to irreversibly extinguish virus in vitro, a feature that distinguishes KP-1461 from all approved antiretroviral agents, and extensive pre-clinical evaluation conditioned the conduct of the phase I-b study performed in HIV-infected individuals reported here.

When individual adverse events were evaluated, headache, nausea, neutropenia and fatigue (or increased fatigue) were the most frequent, with 5 events. Other events were thrombocytopenia and diarrhea, each with 4 events, and dizziness, with 3 reported events for the total KP-1461 group.

Discussion

Safety & Tolerability:These data demonstrate that KP-1461 is generally safe and well tolerated when administered at multiple doses, thus warranting phase 2 efficacy studies.--Most adverse events were mild to moderate in intensity--There were no dose-dependency findings to AEs-- Gradable values for laboratory abnormalities were generally mild to moderate and showed no dose-dependency--Further evaluation of hematologic findings in longer-term studies is warranted --No clinically significant changes noted in serial ECG

Efficacy:Despite the expectation that a longer period of dosing would be required, trends are suggestive of antiviral effect by HIV RNA and RT assay at higher doses. (Formal efficacy analysis was not planned as part of this assessment. Descriptive data only is provided.)

Pharmacokinetics:Findings are supportive of pursuing twice daily dosing. (Full PK data will be presented at European AIDS Conference, Madrid, October 2007.)

Purpose:The purposes of study KP-1461-102 are to determine the safety, tolerability, and pharmacokinetic activity of multiple oral doses of KP-1461 in HIV+ men and women, and to assess any effect of KP-1461 on plasma HIV RNA.

Objectives:To assess the safety and tolerability of oral KP-1461 administered every 12 hours for 14 days (28 doses) to cohorts of HIV+ subjects

To determine the PK profiles of KP-1461 (the inactive prodrug) and KP-1212 (the active drug)

To assess the effects of twice-daily KP-1461 over 14 days on plasma HIV RNA copy number and HIV Reverse Transcriptase activity

STUDY DESIGNMethodsThis was a phase 1-b multi-site, randomized, double-blind, placebo-controlled dose-escalation study. Study population included:• Men and women 18 to 60 years of age• CD4+ cell counts >100cells/mm3• HIV RNA 2,500 to 200,000 copies/mL• Documented exposure to at least two different HAART regimens containing NRTI(s), NNRTI(s), and at least two (2) PIs, excluding low dose Ritonavir, for a minimum of four months each OR documented three class resistance by genotype and/or phenotype AND in the opinion of the investigator, have few if any effective treatment options available.

Four cohorts of 10 subjects each were randomized in a ratio of 4:1 to KP-1461 or placebo, respectively. Successive dose cohorts received 400 mg, 800 mg and 1600 mg of KP-1461 every 12 hours. An additional 10 subjects were enrolled at the 1600-mg dose for a total of 20 subjects at the 1600-mg dose. A fifth cohort of 5 subjects was randomized in a ratio of 4:1 to KP-1461 or placebo, respectively, at a KP-1461 dose of 3200 mg every 12 hours. Data on this cohort is not yet complete.

Subjects were off antiretroviral drugs for at least two weeks prior to the first dose of study drug. Each dose was taken on an empty stomach. Subjects in each cohort were treated for 14 days with an additional 14 days of follow-up. Entry into the next higher dose cohort began when the previous cohort completed enrollment and ≥ 80% of subjects completed dosing plus 1 week of observation. Approval to dose escalate was provided by a Safety Review Committee (SRC). If two or more subjects in a cohort experienced a Grade 3 or 4 toxicity, the SRC reviewed the event to determine whether further dose escalation was safe. If the SRC halted escalation, the previous dose level would be considered the maximum tolerated dose (MTD). Blood was collected for a 12-hour PK profile after the first dose and a 24-hour PK profile after the last dose of KP-1461 (Day 14) and at Days 8, 16, 21 and 28 to determine trough drug concentrations. Routine safety assessments were measured at baseline and on Days 4, 6, 8, 10, 12, 14, 16, 21, and 28. Follow-up safety evaluations occurred at Days 16, 18, 21 and 28. Subjects were able to restart antiretroviral medications after the Day 28 visit. If restarted within 2 weeks of the Day 28 visit, blood was to be collected for viral load and CD4+ count 84 days afterward, if subject agreed to do so.

This study was conducted in accordance with the clinical research guidelines defined in the U.S. 21 CFR Parts 50, 56, and 312, the principles enunciated in the World Assembly Declaration of Helsinki and its most recent amendments, and the principles defined by the International Conference on Harmonization.

I have read with interest and -I'll confess- hope this thread and all the links.

I have a question though.

This med has wiped out the virus completely in cell culture and it's now being tested in humans.

My question is, what happens with the HIV reservoirs such as lymph nodes, brain, liver, ...? even if HIV is extinct in the blood won't the virus in other organs kick in at that point and just keep on replicating itself? I thought that current HAARTS regimens was unable to reach the reservoirs and even though this new med is different I thought it still affected the blood.

NewbieI don't think anyone knows the answer to this question, including the people developing the drug. The issue is mentioned in the interview:

It is up to creative scientists, chemist and virologists, to create drugs that can eradicate HIV. We have many things to contend with -- sanctuary sites, and latent resting reservoirs -- but who is to say that the next generation of drugs should not have eradication as its goal?

And I suspect they are viewing this issue with as much hope as you are. Who knows if perhaps this drug can penetrate beyond the circulatory system - the fact that there were neurological adverse events reported in the first study implies that it might cross the blood-brain barrier. But I think the short answer is: no one knows and there won't be anymore answers until the next study is done. If I've missed something anyone, please feel free to correct me!

This is someones post I read on Thebody.com, but I'm far from a computer genius and for some reason I can't get the link to work so if someone could find out what this is about I would be very thankful.

KP-1461 is doing so well, that koronispharma will start phase 3 within december 2008.

I read something else that said one person will get an extension because they didn't achieve an undetectable viral load during the 124 day's of treatment but they didn't say any thing about all the other people in the study. I had very high hopes for this drug and I would love to know what happened to everyone else during the 124 day's of treatment, I'm sure if someone was eradicated of the virus it would be all over the news and I don't see that, so If anyone else has any new information about this please let us know.

I think that good or bad news this company must be very careful how and when it announces so not hearing anything yet means nothing. Sometimes a scientist in a univ. announces a basic science breakthru in press but almost always this is first presented at science conferences to peers. They always tell thier collegues first to get kudos and because these are the people who would understand it the most. a company has more strict requirements to how and when it announces info if it wants to be respected and get investors. many times a year their are private med tech conferences where the bio tech companies present either alone or in groups to the wall street investment world, hoping to get more investment in hopeful new therapies, i think that the number of breakthrus in last year or two or three is huge and we can all be hopeful and i know i am.

Well, I am not sure if I see the diagram correctly, but it seems that, after 14 weeks taking monotherapy KP-1416, the p24 antigen has drop 3 log to almost undectable.

But that is not the major focus. All HAART med can do that. The most important issue here is: after ceasing KP-1212, how would the patient's viral load and CD4 goes?

This medicine is focus on either 1.eradication of the virus, or 2. If not eradicate, patient may cease the med without viral load bouce back "quickly" or CD4 go down to nadir point "quickly".

Therefore, upon ceasing KP-1416, if patient can keep the viral load low for a while (longer than ususal HAART) or they can help patient to keep CD4 dropping slower than HAART), I would say, it is 60% sucessful.

Moreover, they also need to prove, if not eradicate, that patient can cease taking Monotherapy KP-1416 for, say, a year, and then, when go back to the therapy again, the result is still the same. It means that, patients can take the medicine on and off again and again. This is to prevent patient having long term drug toxcity issues caused by Haart. If they can prove this, I would say, it is 80% successful.

If, they can prove that, after cease taking KP-1416 and the viral load will always be undectable, then I'll say, it is 100% successful. (Although, frankly speaking, I kinda doubt this will happen...I still would cross my finger and wish this miracle become true......)

thanks for trying hahaha, but theres alot of graphs and I'm wondering if anyone can explain what they mean and why would they only let one person keep taking kp-1461 if it works. More recently (April 2008)Safety, Tolerability and Activity of KP-1461http://www.natap.org/2008/Pharm/Pharm_24.htm

Guys, In looking more closely at this article and charts, I believe this data is from one of the much earlier phase 1 studies assessing tolerability and basic pharmacology, which was used to justify the current phase 2. This was a 14 day study and I don't think any data at all has been released on the ongoing phase 2, except that it's not over and one person is doing compassionate continuation. And I wouldn't read too much into that - it could mean that it worked so well that the others don't need it anymore and this one person just needed a few more weeks (this is the hopeful reading...) Or it could mean something totally different, but the data's not out yet.

I agree... this looks like a phase I study results... showing drug concentration in the bloodstream. Because the trial period is short, I think we should be hearing about some phase II data before the end of 2008.

Guys, In looking more closely at this article and charts, I believe this data is from one of the much earlier phase 1 studies assessing tolerability and basic pharmacology, which was used to justify the current phase 2. This was a 14 day study and I don't think any data at all has been released on the ongoing phase 2, except that it's not over and one person is doing compassionate continuation. And I wouldn't read too much into that - it could mean that it worked so well that the others don't need it anymore and this one person just needed a few more weeks (this is the hopeful reading...) Or it could mean something totally different, but the data's not out yet.

If I'm wrong on this, please correct.

I think you are right. The data seem to be from this the phase 1b trial, (NCT00129194 in the clinical trials site):

The phase 1b trial was a study of safety, tolerability and pharmokineticc (PK) of kp 1461, and all tables, graphs and charts seem to be about safety, tolerability and PK, except fot a table with the title DRUG ACTIVITY: HIV RNA ( since the study was not designed to study the efficacy of the drug, i did not understand the meaning of this table, maybe someone could explain).

The trial that will give results on the antiretroviral efficacy of KP 1461is the phase 2a trials:

It is frustrating though, because at this point obviously someone knows something but not one is talking and there's really no way to interpret that unless someone here happens to be in touch with one of the study participants. But it's looking like we'll just have to wait until Dec.

- Some argues that: i) as all the 9 participants of the phase I were multi-resistants ii) that 1 underwent FDA-compassionate use then: the 8 others have got good results, otherwise they will probably have underwent FDA-compassionate use as well

i just got emailed this from a recruiter looking for poz guys... this is going on now!!!!!!

I'm on here to help recruit possible subjects for an experimental HIV eradication drug, KP-1461.

The drug is intended to mutate HIV so much that virus population extinguishes itself due to error catastrophe. The drug is in Phase 2 clinical trials and is sponsored by Koronis Pharmaceuticals. Learn more at www.koronispharma.com

To participate you have to have been on antiviral medication THEN DISCONTINUED treatment for 16 weeks or more.

To find a local facility, go to www.clinicaltrials.gov and type KP-1461 in the search field. All information related to the study, including points of contact will be available.

I read an interview some time back w/the drug investigators and the single compassionate use case was a favor to a guy w/no options left. Otherwise, the study is quite picky about who gets in. I looked at the Clinical Trials site again and nothing has changed... still have very specific requirements to get into this one.

My ID Dr . ( Nick Bellos) is one of the people conducting a study of this drug..I talked briefly with the person ( J Rice) he has conducting the interviews but couldn't get any thing specific except they are seeing some promise here......very narrow focus for participation as already mentioned....said I would not be considered since my ongoing regimen has been overall successful.....I will check with him each time I go for an appointment..( 3 months) would be nice to see a "cure" instead of a "treatment"

In a stunning setback, Project Inform has learned Koronis Pharmaceuticals has stopped two studies of their experimental drug, KP-1461. This decision was based on unexpected results from lab tests and not on safety concerns. Those participating in these studies have been told of these developments.

The lab tests that led to this decision were required by the FDA and were essentially repeats of earlier work done by the company. The tests, called serial passage experiments, exposed HIV to different concentrations of the drug to try and force HIV to grow resistant to it. This helps doctors and researchers understand what changes HIV creates to become resistant. Earlier tests failed to force resistance to KP-1461, so the FDA required Koronis to repeat them until resistance emerged.

The experiments were done by the same team who performed the earlier work. Surprisingly, they found that KP-1461 didn’t show measurable anti-HIV activity, which conflicts with what was seen in earlier lab study. The company then looked at the results from the ongoing studies and found similar results: few people experienced significant reductions in their HIV levels.

Only two people were taking KP-1461 at the time of this discovery. The company informed them of the findings, stopped the KP-1461, and recommended they start a full HIV regimen.

Stephen Becker MD, the lead investigator for Koronis, told Project Inform that the company is, “committed to understanding these discordant results and will attempt to validate the original 2002 research,” on KP-1461. Dr. Becker estimated that it would take at least two months to fully investigate this setback.

KP-1461 is a novel HIV treatment that is supposed to work by speeding up the mutation rate of HIV. In theory, this would lead HIV to mutate so much that it becomes unable to infect cells and replicate. This approach, called terminal mutagenesis,was supported by lab experiments which showed that when HIV was exposed to KP-1461 it eventually mutated itself to death. Many people were skeptical and questioned the wisdom of encouraging HIV to mutate — something every other HIV drug seeks to avoid. Even those who support its development, including Project Inform, have acknowledged the unique hurdles faced by KP-1461 and Koronis.

This setback comes at a time when the pipeline of experimental HIV treatments is drying up. While the past few years have marked an impressive period for new HIV drugs, the next few look thin at best. These disappointing and unexplained results make this situation worse. Project Inform hopes that Koronis can get to the bottom of this vexing mystery and refocus its efforts on developing new treatments against HIV/AIDS. are you kidding me, talk about losing hope I really thought this was gonna work, this was the only thing I was looking forward to, what if you need to take it for a longer period, I honestly thought it would take a couple years to work completely I never thought you would take this drug for a couple months and you would magically be cured I was thinking 2 years or something like that, why would they just stop it and where am I supposed to go from here. http://www.projectinform.org/news/2008/061208.shtml

Activists are more concerned about access to health care for poor people, not the views of insane crazy people. For years I wondered why the loony shouting guy who thought he was Jesus and who lives under the railway bridge near my place was homeless.

Then I met you.

So take your capital letters and shove them up your relevant campaign.

Leit, Paul Dalton of Project Inform who wrote the piece above IS an activist and IS attempting to "shed light" on this story. But the fact is, it's not so incredible. If I had a dime for every agent that entered the drug development pipeline that looked positively amazing in early studies, only to pan out to be a big dud, I'd be a wealthy man. Something obviously went wrong here -- and that's unfortunate. Problem here is that the hype surrounding this compound was always much greater than the actual data supporting it -- and you can thank company-hired publicists and lazy mainstream media for this. Nobody was actually hurt -- aside from a venture capitalist or two -- in the process of this lackluster discovery, so I don't think this really deserves to be chalked up as anything more than it really is... another failed compound.

Paul Dalton of Project Inform who wrote the piece above IS an activist and IS attempting to "shed light" on this story.

Yes, I'm following his valuable work but, if I may venture a remark, he is perhaps a bit "too kind", in the circumstances.

Quote

If I had a dime for every agent that entered the drug development pipeline that looked positively amazing in early studies, only to pan out to be a big dud, I'd be a wealthy man.

Same here! BUT... if you had a billion for every agent that- "proved" to irreversibly estinguish the virus after 15 serial passages in vitro- reached a phase II clinical trial- THEN, retested in vitro (as required by the FDA) the same way as above, turned out to be completely inactivewould you be a billionaire???

This, IMHO, is the big difference between the KP-1461 story and "normal failures"!

Quote

Something obviously went wrong here -- and that's unfortunate.

I strongly hope that Paul Dalton finds out what this "something" is. And, very frankly, I suspect it is not a "scientific something"...

Quote

Nobody was actually hurt

I was, Tim. Maybe I'm credulous but I was actually hurt. As you know, KP-1461 approach was completely different from those of all the drugs we have (and VERY intriguing, to say the least); that's why I found this story so depressing both scientifically and in itself.